化学优化的抗肌球蛋白Fab与螯合聚合物的结合物：蛋白质-聚合物单点共价键的性质对生物分布和梗死定位的重要性。

Chemically optimized antimyosin Fab conjugates with chelating polymers: importance of the nature of the protein-polymer single site covalent bond for biodistribution and infarction localization.

作者信息

Trubetskoy V S, Narula J, Khaw B A, Torchilin V P

机构信息

Center for Imaging and Pharmaceutical Research, Massachusetts General Hospital, Charlestown 02129.

出版信息

Bioconjug Chem. 1993 Jul-Aug;4(4):251-5. doi: 10.1021/bc00022a001.

DOI:10.1021/bc00022a001

PMID:8218480

Abstract

Murine antimyosin Fab fragment was conjugated with 111In-labeled N-terminal-modified DTPA-polylysine using three bifunctional reagents: N-hydroxysuccinimide esters of 3-(2-pyridyldithio)propionic acid (SPDP conjugate), 4-(maleimidomethyl)cyclohexanecarboxylic acid (SMCC conjugate) and bromoacetic acid (BrAc conjugate) for potential localization of experimental myocardial infarction. Using various antibody preparations and a rabbit acute myocardial infarction model the following parameters were observed: (1) an in vitro antigen binding activity of SPDP conjugate = SMCC conjugate > BrAc conjugate, (2) a blood clearance rate of SPDP conjugate > BrAc conjugate > SMCC conjugate, (3) a liver and splenic accumulation of SPDP conjugate > BrAc conjugate > SMCC conjugate, and (4) the infarcted tissue activity showed an accumulation of SMCC conjugate > SPDP conjugate > BrAc conjugate. This study exemplifies the importance of rational chemical design of antimyosin Fab-chelating polymer conjugate for improved target tissue localization in vivo.

摘要

使用三种双功能试剂，将小鼠抗肌球蛋白Fab片段与111In标记的N端修饰的二乙三胺五乙酸-聚赖氨酸结合，用于实验性心肌梗死的潜在定位。这三种双功能试剂分别是：3-(2-吡啶二硫代)丙酸N-羟基琥珀酰亚胺酯（SPDP结合物）、4-(马来酰亚胺甲基)环己烷羧酸（SMCC结合物）和溴乙酸（BrAc结合物）。利用各种抗体制剂和兔急性心肌梗死模型，观察了以下参数：(1) SPDP结合物 = SMCC结合物 > BrAc结合物的体外抗原结合活性；(2) SPDP结合物 > BrAc结合物 > SMCC结合物的血液清除率；(3) SPDP结合物 > BrAc结合物 > SMCC结合物在肝脏和脾脏的蓄积；(4) 梗死组织活性显示SMCC结合物 > SPDP结合物 > BrAc结合物的蓄积。本研究例证了抗肌球蛋白Fab-螯合聚合物结合物的合理化学设计对于改善体内靶组织定位的重要性。